The role of modelling in identifying drug targets for diseases of the cell cycle.

The cell cycle is implicated in diseases that are the leading cause of mortality and morbidity in the developed world. Until recently, the search for drug targets has focused on relatively small parts of the regulatory network under the assumption that key events can be controlled by targeting single pathways. This is valid provided the impact of couplings to the wider scale context of the network can be ignored. The resulting depth of study has revealed many new insights; however, these have been won at the expense of breadth and a proper understanding of the consequences of links between the different parts of the network. Since it is now becoming clear that these early assumptions may not hold and successful treatments are likely to employ drugs that simultaneously target a number of different sites in the regulatory network, it is timely to redress this imbalance. However, the substantial increase in complexity presents new challenges and necessitates parallel theoretical and experimental approaches. We review the current status of theoretical models for the cell cycle in light of these new challenges. Many of the existing approaches are not sufficiently comprehensive to simultaneously incorporate the required extent of couplings. Where more appropriate levels of complexity are incorporated, the models are difficult to link directly to currently available data. Further progress requires a better integration of experiment and theory. New kinds of data are required that are quantitative, have a higher temporal resolution and that allow simultaneous quantitative comparison of the concentration of larger numbers of different proteins. More comprehensive models are required and must accommodate not only substantial uncertainties in the structure and kinetic parameters of the networks, but also high levels of ignorance. The most recent results relating network complexity to robustness of the dynamics provide clues that suggest progress is possible.     

Age effects in coding tasks: Componential analysis and test of the sensory deficit hypothesis.

Multiple forms of a symbol-digit substitution task were used to provide a componential analysis of age differences in coding task performance. The results demonstrated age differences in feature encoding, memory, and visual search. A 2nd experiment was conducted with young adults to investigate a sensory deficit as a locus of age differences. The spatial contrast sensitivity deficit of older adults was simulated on forms by applying a digital filter. Persons in the age-simulated contrast condition performed worse than those in the normal contrast condition. The stimulus degradation effect was linked to visual search speed. The study illustrates the utility of componential analysis and offers direct support for the hypothesis that sensory deficits affect performance on tasks used to assess intelligence (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Kinetics of AuSn4 migration in lead-free solders

The relatively fast diffusion of Au atoms in eutectic PbSn matrix is considered one of the contributing factors to the Au embrittlement problem. In this study, we further investigated the Au embrittlement problem in high-Sn solders. Experimentally, Sn3.5Ag (wt.%) spheres with 500-μm diameter were soldered over the Au/Ni soldering pads. It was found that some of the AuSn₄ needles that formed after reflow inside the solder migrated back to the solder/pad interface during thermal aging. However, the migration kinetics in high-Sn solders was slower compared to that in eutectic PbSn. The difference in migration kinetics of AuSn₄ in eutectic PbSn and SnAg was ascribed to the difference in the magnitudes of the Au flux and the Ni flux. In eutectic PbSn, the Au flux was much greater than that of the Ni flux, and the Au and Ni flux were in the same order of magnitude in eutectic SnAg. The relative magnitude of the Au and Ni flux changed in eutectic PbSn and SnAg because the homologous temperatures of PbSn and SnAg were different.     

Yielding- and fracture behaviour of ferritic steels in the transition region of quasistatic to dynamic loading

This paper presents results of investigations on the influence of loading rate on yielding and fracture behaviour of ferritic steels. The range of loading rates was below a certain level at which a special stress wave analysis is required. Concerning the yielding behaviour it was found, that the yield strength can be predicted by the model of thermally activated flow. The strain hardening dσ/dε appeared to be independent of strain rate, if adiabetic heating can be neglected. Concerning the fracture behaviour it is demonstrated that the K_lc-T-curves are shifted to higher temperatures with increasing loading rate. The temperature shift could be correlated with the strain rate sensitivity m = d lnσ/d lnε. The ductile/brittle transition temperature increases with incrasing loading rate. For the upper shelf region crack resistance curves as a function of loading rate are presented. It is shown that the crack length can be determined using the key-curve-method. A slightly increasing tendency of the evaluated J_R-curves was found.     

Clinical trial of a new lightwand device (Trachlight) to intubate the trachea

BACKGROUND: Transillumination of the soft tissue of the neck using a lighted stylet (lightwand) is an effective and safe intubating technique. A newly designed lightwand (Trachlight) incorporates modifications to improve the brightness of the light source as well as flexibility. The goal of this study was to determine the effectiveness and safety of this device in intubating the trachea of elective surgical patients. METHODS: Healthy surgical patients were studied. Patients with known or potential problems with intubation were excluded. During general anesthesia, the tracheas were intubated randomly using either the Trachlight or the laryngoscope. Failure to intubate was defined as lack of successful intubation after three attempts. The duration of each attempt was recorded as the time from insertion of the device into the oropharynx to the time of its removal. The total time to intubation (TTI), an overall measure of the ease of intubation, was defined as the sum of the durations of all (as many as three) intubation attempts. Complications, such as mucosal bleeding, lacerations, dental injury, and sore throat, were recorded. RESULTS: Nine hundred fifty patients (479 in the Trachlight group and 471 in the laryngoscope group) were studied. There was a 1% failure rate with the Trachlight, and 92% of intubations were successful on the first attempt, compared with a 3% failure rate and an 89% success rate on the first attempt with the laryngoscope (P not significant). All failures were followed by successful intubation using the alternate device. The TTI was significantly less with the Trachlight compared with the laryngoscope (15.7 +/- 10.8 vs. 19.6 +/- 23.7 s). For laryngoscopic intubation, the TTI was longer for patients with limited mandibular protrusion and mentohyoid distance, with a larger circumference of the neck, and with a high classification according to Mallampatti et al. However, there was no relation between the TTI and any of the airway parameters for Trachlight. There were significantly fewer traumatic events in the Trachlight group than in the laryngoscope group (10 vs. 37). More patients complained of sore throat in the laryngoscope group than in the Trachlight group (25.3% vs. 17.1%). CONCLUSIONS: In contrast to laryngoscopy, the ease of intubation using the Trachlight does not appear to be influenced by anatomic variations of the upper airway. Intubation occasionally failed with the Trachlight but in all cases was resolved with direct laryngoscopy. The failures of direct laryngoscopy were resolved with Trachlight. Thus the combined technique was 100% successful in intubating the tracheas of all patients.     

Flaw density examinations of a clad boiling water reactor pressure vessel segment

As part of the Oak Ridge National Laboratory's Heavy-Section Steel Technology Program, studies have been conducted to determine flaw density in a section of reactor pressure vessel cut from the Hope Creek Unit 2 vessel. This boiling water reactor vessel was never in service. One objective was to evaluate the approximate 0.7- by 3-m (2- by 10-ft) segment of the vessel provided using ultrasonic flaw detection methods performed with both ASME Code techniques and supplemental ultrasonic methods. A second objective was to evaluate the inner surface stainless steel cladding for cracks with a high sensitivity penetrant examination. Both objectives were successfully completed. Five Code-recordable indications were detected ultrasonically; however, all were found to be anomalies associated with the cladding. One flaw was detected by the supplemental ultrasonic tests, and it was analyzed destructively. This flaw was pipelike indication, about 20 mm (0.8 in.) long extending along the length of the longitudinal weld in which it was located and was about 20 mm below the cladding surface. The flaw had a through-wall dimension (or length) of about 6 mm (0.24 in.) for an approximate 3-mm (0.1-in.) distance along the 20-mm major length. No flaws were detected by the penetrant examination of the cladding surface.